Mechanisms of Teleomere-Mediated Emphysema

项目总结/摘要 肺气肿在美国和世界范围内造成巨大的健康负担。吸烟和 高龄是其发展的最大风险因素，然而， 肺气肿的易感性及其与年龄相关的发病在很大程度上是未知的。端粒是DNA， 保护染色体末端的蛋白质结构。细胞每次分裂时，端粒会缩短变短 端粒激活DNA损伤反应，引发细胞死亡或细胞周期停滞。端粒长度是 端粒在人群中具有异质性，并随着年龄的增长而缩短;但端粒与肺气肿之间的联系 还没有在动物模型中探索过。这一建议建立在我们已经产生的令人兴奋的初步数据的基础上， 端粒短的小鼠更容易受到香烟烟雾（CS）的影响并发展为肺气肿。我们有 发现短端粒限制了肺上皮细胞在损伤后修复和恢复的能力。这个项目 将使用端粒功能障碍的小鼠作为研究肺气肿生物学的模型系统， 其发病机制的基础。在第一个目标中，我们将从基因上移除下游的一个关键点， 调节DNA损伤后细胞周期停滞，并测试这是否挽救端粒诱导的CS易感性。 在第二个目标中，我们将建立一个新的模型来探索端粒功能障碍在人类中的后果。 肺内的单个细胞类型，以确定肺气肿易感性的细胞基础。最后在 第三个目标，我们将研究介导端粒诱导的肺重构的分泌蛋白，这是 这是本研究的独立部分。拟议的研究有可能确定关键的 导致肺气肿发病的途径。一旦确定，这些介质可能是 用于治疗或预防肺气肿。我选择了一个优秀的环境和一群导师， 完成我最后几年的训练在培训期间，我预计环境和 我制定的额外培训计划将使我准备建立一个独立的小组， 转化肺研究的重大进展。

Project Summary/Abstract Emphysema causes an enormous health burden within the United States and worldwide. Smoking and advanced age are the biggest risk factors for its development, yet the genetic factors that contribute to emphysema susceptibility and its associated age-related onset are largely unknown. Telomeres are DNA and protein structures that protect the ends of chromosomes. Each time a cell divides, telomeres shorten and short telomeres activate a DNA damage response that triggers cell death or cell cycle arrest. Telomere lengths are heterogeneous in the population and shorten with age; but the link between telomeres and emphysema has not been explored in animal models. This proposal builds on exciting preliminary data we have generated that mice with short telomeres are more susceptible to cigarette smoke (CS) and develop emphysema. We have found that short telomeres limit the ability of lung epithelial cells to repair and recover after injury. This project will use mice with dysfunctional telomeres as a model system for studying emphysema biology and explore mechanisms that underlie its pathogenesis. In the first aim, we will genetically remove a key downstream regulator of cell cycle arrest following DNA damage and test if this rescues telomere-induced CS susceptibility. In the second aim, we will generate a new model to probe the consequences of telomere dysfunction in individual cell types within the lung to define the cellular basis for the emphysema susceptibility. Finally, in the third aim, we will examine the secreted proteins that mediate telomere-induced lung restructuring; this is the subject of the independent portion of this research. The proposed studies have potential to identify key pathways that contribute to emphysema pathogenesis. When identified, these mediators could potentially be targeted to treat or prevent emphysema. I have chosen an outstanding environment and group of mentors to complete the final years of my training. During the training period, I anticipate that the environment and additional training plan I have formulated will prepare me to establish an independent group that can make significant advances in translational lung research.